The Epidemiology, Outcomes, and Costs of Contemporary Kidney Transplantation




Abstract


Since the first kidney transplant procedure in 1954, evolution in immunosuppression management, surgical practice, and organ preservation has improved transplant outcomes and reduced perioperative morbidity. As a result, kidney transplantation has been established as the best treatment option for patients with renal failure, providing superior survival, quality of life, and cost savings. Recognition that the benefits extend to older patients, diabetic candidates, and those with other significant medical or surgical comorbidities has contributed to growing demand for kidney transplant. Unfortunately, the supply of living donor organs appears to have plateaued and deceased donor organs have not increased sufficiently, resulting in progressive growth in the kidney transplant waiting list. In addition, the population of patients with high degrees of allosensitization has increased, propelled in part by changes in Organ Procurement and Transplantation Network policy that prioritize highly sensitized patients and a growing population seeking retransplantation. Transplant centers are now expected to achieve exceptional survival outcomes despite the increasing complexity of the recipient population and the donor pool. Centers that fail to meet performance standards face regulatory censure and possible closure. Compounding this risk, current reimbursement for kidney transplant services correlates poorly with the cost of the procedures, threatening the financial viability of transplant care. Innovative strategies are needed to ensure that risk aversion and adverse financial pressure do not limit the ability of transplant programs to continue to offer the miracle of transplantation to all patients who can benefit.




Keywords

deceased donation, economics, kidney transplantation, living donation, outcomes, performance, risk factors

 






  • Outline



  • Introduction, 539



  • Kidney Transplant Candidates: Characteristics and Trends, 539



  • Changes in the Transplant Waiting List, 540



  • Transplant Recipients: Characteristics and Trends, 540



  • Changes in Deceased Donor Organ Characteristics, Allocation, Utilization, and Access, 541



  • Living Donor Transplantation, 542



  • Immunosuppression: Trends and Current Practice, 543




    • Induction Immunosuppression, 543



    • Maintenance Immunosuppression, 544




  • Complications of Kidney Transplantation, 546



  • Posttransplant Outcomes, 547




    • Acute Rejection, 548



    • Graft Survival, 549



    • Patient Survival, 549




  • Center Performance Grading, 549




    • Centers for Medicare & Medicaid Services, 549



    • Effect of Performance Monitoring, 549




  • Unmeasured and Novel Risk Factors, 550



  • Economics of Kidney Transplantation, 551



  • Economic Implications of Recipient Characteristics, 552



  • Economic Implications of Donor Characteristics, 552



  • Economic Implications of the Current Kidney Allocation System, 553



  • Economic Implications of Practice Innovation: ABO- and HLA-Incompatible Kidney Transplantation, 553



  • Conclusions, 553




Introduction


Although the successful transplantation of the Herrick twins in 1954 established the feasibility of kidney transplantation, widespread adoption required the introduction of effective immunosuppression medications, the ability to avoid preformed anti-HLA antibodies through crossmatching, and the systematic allocation of donated organs. Over the ensuing 70 years, kidney transplant outcomes have improved, and graft survival rates now routinely exceed 96% at 1 year. Long-term patient survival with kidney transplant significantly exceeds that achieved by hemodialysis at a lower cost to society. However, changes in recipient characteristics, donor quality, and treatment strategies have affected the resources required for successful transplantation, increasing the cost of transplant, especially for novel treatment strategies.




Kidney Transplant Candidates: Characteristics and Trends


The complexity of candidates on the waiting list has changed markedly over the past 20 years. Once used primarily in young patients with glomerular disease, kidney transplant is now the treatment of choice for patients with long-standing chronic illness. Diabetes is the leading etiology of kidney failure among listed candidates (36%), followed by hypertension (24%), and glomerulonephritis (14%). Successful kidney transplantation is routinely performed in patients previously believed to be too high risk to benefit, including the elderly and patients with significant pretransplant comorbidities. Transplant in patients aged 65 years and older improves survival compared with remaining on dialysis. Even transplant recipients aged 70 years and older experience lower mortality risk than waitlisted dialysis patients (age 70 to 74: hazard ratio [HR], 0.59; age ≥75: HR, 0.58). As a result, patients older than age 50 have become the fastest-growing cohort of waitlisted candidates, increasing from 34,871 patients in 2005 (56% of the list) to 64,408 in 2015 (66% of the list). The percentage of candidates aged 65 years or older rose from 14.5% in 2005 to 22% in 2015. Patients previously excluded from transplant due to medical comorbidities can now be successfully treated. Gill and colleagues demonstrated a significant survival benefit from transplant among patients who with existing ischemic heart disease (7.9 years), peripheral vascular disease (7.9 years), and or congestive heart failure (6.7 years) compared with long-term dialysis. These authors also demonstrated a 48% reduction in the risk for death by 1-year posttransplant in patients with body mass index (BMI) >40 kg/m 2 compared with a 66% reduction in patients with BMI <40 kg/m 2 . Patients with prior failed allografts in need of retransplantation now comprise 13% of the waiting list, as the outcomes after retransplantation have improved sufficiently to consider this treatment option.


The proportion of candidates on the waiting list with more than 5 years of dialysis dependence increased from 11.4% in 2005 to 15.7% in 2015. Longer pretransplant dialysis contributes to waitlist mortality and is a risk factor for poor outcomes after transplant. Although prolonged waiting times contribute to the extended periods of dialysis, delay in timely referral for transplant evaluation also remains a major barrier to transplantation. Almost half of the patients newly listed for transplant have been on dialysis for more than 4 years. Lower socioeconomic status was associated with lower kidney transplant access, and residing farther from a transplant center or in rural regions is associated with lower deceased donor transplant access. Members of racial and ethnic minorities, such as African Americans, face barriers to transplant evaluation and delays in listing, exacerbating racial disparities in access to transplant. These differences begin at the local level. One recent study examined referral patterns for incident dialysis patients in Georgia and found that although the average rate of referral for evaluation within 1 year of dialysis was only 24%, rates varied from 0% to 75% across dialysis centers. Dialysis facilities with the lowest transplant referral rates were more likely to treat patients living in high poverty neighborhoods, had higher patient-to-social worker ratios, and were more likely nonprofit.




Changes in the Transplant Waiting List


Unfortunately, the limited supply of deceased and living donor organs has not kept pace with growing demand for kidney transplant. As of May 2017, more than 117,000 patients were waiting for kidney transplantation, compared with 62,166 in 2005. The average national waiting time for a deceased donor organ exceeds 3.5 years. Despite the directive of the “Final Rule” issued by the Department of Health and Human Services for the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) to reduce disparity in access to transplantation, marked differences in average waiting time and transplant rates persist. Patients in some areas of the United States experience disparities in transplant access, due, in part, to differences between the local supply of organs and demand for transplant. Other factors that contribute to differences in waiting times include the degree of competition between centers and aggressiveness in organ acceptance practices. Rates of living donor transplant also vary markedly, and are reduced in areas with low socioeconomic status, high minority populations, and greater obesity.


The wait for transplant for an individual candidate is influenced by biological factors as well as regional variation in waiting list size and organ availability. High levels of allosensitization are associated with reduced access to transplant due to greater difficulty identifying compatible organs. Although the recent revision of the US kidney allocation system (KAS; discussed later) has been effective in increasing decreased donor transplant rates among the most highly sensitized (panel reactive antibody [PRA] level 98% to 100%), from 7% per 100 patient-years in 2013 to almost 30% in 2015, patients with slightly lower levels of sensitization continue to have reduced access to transplantation. The incidence of highly sensitized patients is likely to further increase as patients with prior transplants are considered for retransplantation.




Transplant Recipients: Characteristics and Trends


In 2015, 18,597 adult and pediatric kidney transplants, including multiorgan transplants, were performed in the United States, an increase from 17,388 in 2005. Living donor transplant constituted 30% of the transplants in 2015, down slightly from its peak in 2004. Recipient demographics mirror that of the waiting list, as older patients now comprise a higher fraction of transplant recipients. Recipients older than 60 years of age increased from 15% in 1995 to 2000 to 31.5% in 2011 to 2016 ( Fig. 34.1 ). The proportion of non-Caucasian recipients has increased slowly over recent decades: 49% of recipients transplanted from 2010 to 2015 were white compared with 60.8% in 1995 to 2000. Mirroring the obesity epidemic in the general population, obese transplant recipients (BMI >30 kg/m 2 ) increased from 13.5% between 1995 and 2000 to more than 33% of recipients in 2011 to 2016. Half of the transplants were performed in recipients whose end-stage renal disease (ESRD) was reported to be caused by diabetes and hypertension. Hypertension is also the most commonly reported comorbid condition among transplant recipients (72%), followed by diabetes (32%).




FIG. 34.1


Evolution in the age distribution of US kidney transplant recipients over time. Prepared by the authors from Scientific Registry of Transplant Recipients data through December 2016.


The proportion of deceased donor kidney transplants in recipients with calculated panel reactive antibody (cPRA) 98% to 100% rose from 4.8% in 2014 to 14.6% in 2015, reflecting changes in the KAS to increase access for patients with highest levels of allosensitization. Recipients with cPRA 80% to 89% declined from 6.6% in 2014 to 3.2% in 2015, whereas recipients with a cPRA from 90% to 97% remained the same.




Changes in Deceased Donor Organ Characteristics, Allocation, Utilization, and Access


The growing organ shortage has led to increased recovery of deceased donor organs with a higher risk of graft failure, delayed graft function (DGF), and primary nonfunction. Factors associated with higher rates of early kidney graft failure include donor age, comorbidities, premortem renal function, and associated medical comorbidities. The use of kidneys from donors older than 50 years of age, and particularly older than 65 years of age, is associated with increased risk for DGF, acute rejection, and graft loss. Grafts from older donors have more age-related changes of atherosclerosis and fewer functional nephrons. Therefore they have limited reserve to adapt to new insults in the setting of kidney transplant. It also is proposed that kidneys from older donors are more immunogenic than kidneys from younger donors, and thus have higher risk for rejection. Despite these effects on graft outcomes, the use of donors older than 50 years of age remained stable (approximately 25% of all decreased donors) between 2004 and 2015. The proportion of deceased donors with history of hypertension also remained at approximately 25% during this period. Most organs are recovered after brain death, a mechanism of death that offers the opportunity to sustain organ perfusion with oxygenated blood until the time of actual recovery followed by immediate cooling to minimize ischemic injury. Donors who do not meet the legal definition of brain death for whom organs are recovered after cessation of cardiac activity are known as donation after cardiac death (DCD). DCD donors are classified using the Maastricht categorization of controlled and uncontrolled cardiac death. Controlled DCD donors are those who suffer cardiac arrest after planned and witnessed withdrawal of support. Uncontrolled donors are those whose heart has stopped before arrival to the hospital, with or without successful resuscitation. In the United States, the vast majority of DCD donors are controlled donors. DCD has been associated with higher rates of DGF and primary nonfunction. After DGF recovery, however, recipients of DCD kidneys have long-term allograft and survival comparable to those of recipients of kidneys recovered after brain death, especially when organs are procured from donors younger than 50 years of age. DCD utilization has increased from 10% in 2005% to 18% in 2015, but varies widely between transplant programs and donation service areas.


In December 2014, the OPTN implemented changes to the US KAS designed to improve the utility of deceased donor kidneys and equity in transplant access. As noted previously, sensitization is a barrier to transplant access because it reduces the likelihood of identifying an organ against which the candidate does not have preformed donor-specific antibodies. For minority race candidates, such as African Americans, who face barriers to transplant evaluation and listing, delays in listing reduces allocation priority and exacerbate racial disparities in access to transplant. Important changes incorporated in the revised KAS include defining the start of waiting time at the date of chronic dialysis initiation for patients who were already on dialysis. This change provides better equity for patients who were referred late or had delayed access to transplant services. Candidates receive an allocation point for every year of dialysis before registration. A sliding scale of increasing allocation points was incorporated for the most highly sensitized patients, such that candidates with calculated cPRA scores of 98%, 99%, and 100% receive 24.4, 50.1, and 202.1 points, respectively. This priority is designed to improve access to potentially compatible organs. To improve access for blood type B candidates, they are now being offered blood type A2 and A2B kidneys at transplant programs willing to accept such organs, based on evidence that transplantation care be safely performed without preconditioning treatments as the A2 antigen has a low level of expression on the cell membrane, rendering the A2 kidney similar to a blood group O kidney.


The revised KAS also was designed to increase transplant utility through incorporation of “longevity matching” based on scores for organ quality and expected recipient survival. The previous binary division of deceased donors as standard and expanded criteria donors was replaced with continuous, more granular grading of organ quality using the kidney donor risk index (KDRI) based on 10 donor characteristics: age, height, weight, ethnicity, history of hypertension, history of diabetes, cause of death, serum creatinine, hepatitis C serology (HCV), and DCD. The KDRI provides an estimate of the relative risk for posttransplant kidney graft failure from a particular deceased donor compared with the median donor in the previous calendar year. Kidney donor profile index (KDPI) is estimated from KDRI as a percentage from 0% to 100%, designed to rank the quality of a specific donor organ relative to other kidneys; lower KDPI values are associated with better donor quality and vice versa. Kidneys with KDPI >85% are comparable to previously designated expanded criteria kidneys. A continuous scale also was developed to compute estimated posttransplant survival (EPTS) in transplant candidates based on candidate age, length of dialysis, diabetes, and prior solid organ transplant status. Lower EPTS score (on a scale ranging from 0% to 100%) indicates that the candidate is expected to benefit from more years of graft function compared with candidates with higher scores. To optimize utility, the revised KAS prioritizes candidates with the highest predicted posttransplant benefits (EPTS ≤20%) to receive offers for kidneys from donors with KDPI <20%. Assessment of the effects of the revised KAS over the first year postimplementation demonstrated the following trends:




  • Increased transplant rate among highly sensitized candidates (cPRA >98%), from 7 per 100 waitlist years in 2014 to 27 per 100 waitlist years in 2015.



  • Increased likelihood of transplantation among candidates aged 18 to 40 years (adjusted hazard ratio [aHR], 1.47; 95% confidence interval [CI], 1.38 to 1.57), but reduced access for candidates aged >50 years (aHR, 0.93; 95% CI, 0.87 to 0.98 for age 51 to 60 and aHR, 0.90; 95% CI, 0.85 to 0.96 for age >70).



  • Increases in the proportions of African American and Hispanic transplant recipients. Two-year post-KAS analysis demonstrates that African Americans and Hispanics are now transplanted in proportion to their representation on the waitlist. Importantly, these estimates do not consider disparities in access to transplant services and initial listing.



  • Increase in the correlation between donor age and recipient age, from 0.35 to 0.38.



  • Greater likelihood of waitlisted candidates with the top 20% of life expectancy (EPTS <20%) to undergo transplant with shorter waiting time: approximately 50% of these candidates underwent transplant by 3.2 years after listing, compared with an average waiting time of 4.5 years under the prior policy.



The use of kidneys from infection risk donors (IRD) also has expanded in light of the ongoing organ shortage and the epidemic in opiate overdose-associated mortality. These are kidneys recovered from donors with behaviors associated with HIV, hepatitis B, and HCV infection, generally intravenous drug use, incarceration, and certain sexual practices. These behaviors were formally defined by the US Public Health Services (US PHS) and must be disclosed to potential recipients. A change from the Centers for Disease Control and Prevention criteria increased the number of organs defined as being recovered from “increased risk” donors. Strikingly, 20% of kidneys are now classified as US PHS increased risk. Notably, the vast majority of organs are screened with nucleic acid testing (NAT) to identify the presence of HIV or HCV, which has dramatically reduced the risk for unintentional disease transmission during the “window period.” Risk prediction tools to compare outcomes with dialysis may guide use of IRD organs in patients who can benefit. IRD kidneys often are high-quality organs from young donors with excellent long-term survival. Although not directly factored into the calculator, it is also notable that both HIV and HCV are treatable infections, such that the rare transmission can be managed, which is a consideration compared with the high mortality of dialysis. The UNOS Disease Transmission Advisory Committee (DTAC) recently released an educational resource to help patients and providers understand the risks and benefits associated with these organs. Kidneys from donors with known HCV can benefit HCV-positive recipients by markedly reducing time to transplantation. Patients with HCV who accept an HCV-positive kidney wait an average of 395 days less than those who wait for an HCV-negative kidney. Recent experimental protocols have been introduced to allow transplantation of HCV-positive donor organs into HCV-negative recipients to expand access to organ from these donors, provided that recipients undergo posttransplant antiviral treatment.


Other nonstandard organs that may provide benefit to some patients include kidneys procured from donors with high terminal creatinine due to acute tubular necrosis. These organs are frequently discarded. Analysis of the UNOS database from 1995 to 2007 showed that among donors with terminal creatinine >2 mg/dL, neither kidney was recovered in 44%, whereas when terminal creatinine was ≤1.5 mg/dL neither kidney was recovered in only 2%. However, emerging data show these kidneys can be safely used with recognition that a period of posttransplant dialysis will likely be needed. In one single-center experience, transplants from donors with terminal creatinine >2 mg/dL had a higher rate of DGF (66%) and longer DGF (median 10 days) compared with transplants from donors without acute kidney injury (DGF 27%, with median duration 8 days), but similar estimated glomerular filtration rate and graft survival at 1 year posttransplant.


Unfortunately, the discard rate (i.e., the proportion of organs recovered but not used) has remained at approximately 20% despite the organ shortage and the changes in KAS described previously. The discard rate does vary with donor factors and quality measures, increasing with donor age and higher KDPI. Notably, the discard rate begins to rise earlier than risk for adverse outcomes: Whereas graft failure and DGF risk starts to accelerate at KDPI >70, the discard rates rise in a linear manner at KDPI >40 ( Fig. 34.2 ). A caveat to this comparison is that transplant outcomes apply to the selected subset of higher risk organs that are used, but the observation raises that use should be considered. Despite higher rates of graft failure, high KDPI organs provide substantial benefit in appropriate populations. A recent study of national registry data by Massie et al. showed that high-KDPI transplant, defined as KDPI >70, was associated with increased short-term death risk over 6 months, but better long-term survival, compared with waiting for a higher-quality organ among older patients, diabetics, and those living in regions with prolonged waiting times. This study also found that the highest-risk organs (KDPI 91 to 100) benefit patients older than 50 years of age at centers with waiting times longer than 3 years.




FIG. 34.2


The discard rate rises more rapidly with higher KDPI than graft failure and DGF rates. Prepared by the authors from Scientific Registry of Transplant Recipients data from 2010 to 2016. DGF , Delayed graft function; KDPI , kidney donor profile index.




Living Donor Transplantation


Living kidney donors can be related, unrelated, nondirected, or participants in donor exchange (kidney paired donation [KPD]) programs. Living donor transplantation provides benefits over deceased donor kidney transplantation including faster access to transplant, which reduces time on dialysis and its associated risks, as well as superior long-term patient and allograft survival at the lowest cost. Unfortunately, living donor kidney transplantation in the United States has declined from a peak of 6000 in 2004 to current rates of approximately 5500 per year. Multiple barriers to living donor transplantation exist, including the transplant candidate’s ability to identify a willing donor, ensuring donor health and proper selection, and uncompensated costs for the donor. Based on clear evidence of recipient benefit and surveys supporting positive public perceptions of living donation, a number of recent initiatives are underway to increase awareness of living donor transplantation and reduce disincentives, including a 2015 American Society of Transplantation Consensus Statement promoting living donor transplantation as the “best treatment option” for eligible patients with kidney failure.


The pool of potential living donors has been expanded through the widespread access to laparoscopic donor nephrectomy and the development of KPD programs for patients with willing but biologically incompatible donors. Laparoscopic nephrectomy offers reduced surgical risk, pain, and cost. The laparoscopic approach also has enabled expansion of the living donor pool to older patients and has reduced the fear of donation. KPD programs apply algorithms to exchange kidneys among two or more pairs of incompatible donors and recipients so that all candidates receive compatible organs. Paired donation has been the fastest growing living donor transplant modality, and currently comprises approximately 10% of living donor transplants per year. Survey of potential donors supports strong willingness of potential donors to participate in KPD to facilitate transplant access for their intended recipient. However, it is widely believe that KPD is underused: It is estimated that if all centers used paired donation at the rate of high-performing centers, another 1000 transplants could be performed per year. Entry of compatible pairs into KPD has been suggested as an approach to increase the pool of potential matches. Entry of biologically compatible pairs in KPD systems may result in the compatible recipient receiving a better matched organ or organ from a younger donor. Best practices for the living kidney donor selection are out of the scope of this chapter; however, a comprehensive review is found in the 2017 Kidney Disease Improving Global Outcomes (KDIGO) “Guideline on the Evaluation and Care of Living Kidney Donors.”




Immunosuppression: Trends and Current Practice


Induction Immunosuppression


The success of kidney transplantation is largely the result of the advances of immunosuppression including better induction therapy and maintenance regimens. The KDIGO guideline recommends induction therapy in all kidney transplant recipients (1A). This guideline also recommends interleukin-2 receptor antibody (IL2rAb) for first-line induction therapy (1B), while offering a class 2B recommendation for use of cell-depleting agents in patients considered high risk for acute rejection. A higher risk for rejection has been associated with African American heritage, significant allosensitization, history of prior transplantation, longer cold ischemic time, younger recipient age, and DGF. In addition, the choice of maintenance medications influences the need for induction therapy. In 2015, 91% of kidney transplant recipients received induction therapy. Use of IL2rAb fell from 35% in 2004% to 20% in 2015, whereas use of T-cell depleting agents (including thymoglobulin, alemtuzumab) continued to increase, from 39.5% in 2004 to 70% in 2015. The percentage of recipients receiving no induction therapy continued to decline from 22% in 2004 reaching a low of 9.1% in 2015 ( Fig. 34.3 ).




FIG. 34.3


National trends in kidney transplant induction over time. IL2rAb , interleukin-2 receptor blocking antibodies.

Reproduced with permission from Dharnidharkaa VR, Naik AS, Axelrod DA, et al. Center practice drives variation in choice of U.S. kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018;31:198-211.


Choice of induction therapy should be determined based on patient and donor characteristics. For instance, black, highly sensitized, or recipients who experience DGF are, appropriately, more likely to be treated with cell-depleting agents (alemtuzumab, thymoglobulin) than IL2rAb ( Fig. 34.4 ). Alemtuzumab is more commonly used with steroid-free maintenance regimens (tacrolimus and antimetabolite), whereas induction may not be used in patients on triple maintenance therapy. Although low-risk patients, such as 2 haplotype-matched white recipients, may be transplanted safely with no induction, the majority of patients seem to benefit from induction treatment. However, recent evidence suggests that center practice patterns, rather than patient and donor characteristics, dominate the decision about whether or not to use induction agents, and if so, which one.




FIG. 34.4


National trends in kidney transplant induction by recipient immunological risk profile. ALEM , Alemtuzumab; IL2rAb , interleukin-2 receptor blocking antibodies; TMG , thymoglobulin. High risk was defined as black race, PRA >20, or retransplantation.

Reproduced with permission from Dharnidharkaa VR, Naik AS, Axelrod DA, et al. Center practice drives variation in choice of U.S. kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018;31:198-211.


Maintenance Immunosuppression


Initially, maintenance immunosuppression was relatively standardized (cyclosporine, azathioprine, and corticosteroids) due to limited options available to transplant physicians. The nephrotoxicity of cyclosporine was recognized as a limiting factor in improving the long-term outcomes of kidney transplantation, as was the risk for skin cancer associated with azathioprine. The introduction of tacrolimus, mycophenolate, mammalian target of rapamycin inhibitors (mTORi: sirolimus and everolimus) and belatacept has now given transplant providers a wider variety of choices and the potential for tailoring to optimize individual patient outcomes. However, in reality, the variation of regimens among transplant centers is largely driven by center practice and preference rather than patient demographic and transplant characteristics ( Fig. 34.5 ). In national studies, despite similar patient and donor demographics, there is wide variation in selection of antirejection regimen. This variation emphasizes the need for more evidence-based practice, as well as collaborative clinical trials and secondary data analyses of contemporary practice to optimize posttransplant outcome. Here, we will review the trends of individual agent use and immunosuppression regimen preference among the transplant centers in the United States.




FIG. 34.5


Proportion of US patients receiving one of six mutually exclusive immunosuppression regimens during months 6 to 12 posttransplant. Each horizontal bar represents an individual center within US regions ordered by the proportion of patients who received triple immunosuppression (Tac + MPA/AZA + Pred). Overall percentage of regimen use at patient-level across centers: Tac + MPA/AZA + Pred, 33.8%; Tac + MPA/AZA (No Pred), 25.8%; Tac without MPA/AZA, 11.3%; SRL-based, 9.9%; CSA-based, 7.8%; and other regimens, 11.6%. AZA , Azathioprine; CSA , cyclosporine; MPA , mycophenolate; Pred , prednisone; SRL , sirolimus; Tac , tacrolimus.

Reproduced with permission from Axelrod D, Naik AS, Schnitzler MA, et al. National variation in use of immunosuppression for kidney transplantation: a call for evidence-based regimen selection. Am J Transplant. 2016;16:2453-2462.


Calcineurin inhibitors (CNIs) continue to form the cornerstone of maintenance immunosuppression medications despite the modest adoption of belatacept at some transplant centers. Among CNIs, tacrolimus has been the dominant medication and its use increased from 75% in 2004 to reach 97% in 2015. Tacrolimus has two new extended-release formulations to allow once-per-day dosing. However, the immediate-release formulation remains the most commonly used, possibly because it is available as a generic option. Mycophenolate has been established as the antimetabolite medication of choice, with one of two formulations (mycophenolate mofetil, mycophenolate sodium) comprising more than 95% of antimetabolite use. Less than 5% of recipients are prescribed azathioprine in current practice. Although the mycophenolate formulations are believed to differ in side-effect profile, clinical outcomes have not been shown to differ significantly.


Modern renal transplant immunosuppression is generally based on a combination of two or more agents. One-third of kidney transplant recipients transplanted from 2004 to 2010 received triple immunosuppression composed of tacrolimus, an antimetabolite, and corticosteroids. The second most commonly prescribed regimen in this period was tacrolimus and antimetabolite (steroid avoidance) in 26% of the recipients, followed by tacrolimus alone or tacrolimus plus prednisone (antimetabolite sparing) in 11.3%, mTORi-based (with or without CNI) in 9.9%, and cyclosporine-based in 7.8%. Although the use of these regimens varies significantly among transplant centers, the use of triple-therapy immunosuppression is more likely among patients with higher immunological risk such as highly sensitized patients, retransplant recipients, and those with a history of glomerulonephritis. The use of mTORi-based regimens is more likely in patients with lower GFR at 6 months posttransplant. Overall, mTORi use in kidney transplant recipients declined from approximately 15% in 2004% to 5% in 2015. This decline is mainly driven by recognition of associations with increased risk for poor wound healing, acute rejection, and proteinuria without realization of substantial benefits in long-term allograft survival.


Despite the wide variety of choices of immunosuppression medications, long-term graft survival remains limited by chronic transplant glomerulopathy, interstitial fibrosis/tubular atrophy, inflammation, and subclinical cellular and antibody medicated rejection. Complications of immunosuppression, including infection and malignancy as discussed here, pose challenges for long-term patient survival. Further advances in medications and new strategies for posttransplant monitoring, being explored in the evolving field of biomarkers, are needed to improve the long-term outcomes after kidney transplantation.




Complications of Kidney Transplantation


The increased potency of contemporary immunosuppression has yielded substantial reductions in acute rejection rates. In the early 1980s, 50% to 60% of renal allograft recipients experienced at least one acute rejection episode compared with less than 15% today. In the ELITE-Symphony study, which simultaneously compared low- or high-dose cyclosporine-based to tacrolimus-based or sirolimus-based regimens, the acute rejection rates and graft failure rates were much higher in the nontacrolimus-based arms, contributing to widespread adoption of tacrolimus-based regimens. However, the benefits of preventing acute rejection are balanced by the risks for overimmunosuppression, including infection and malignancy. In this section, we review the epidemiology and effects of clinical complications such as infections, malignancy, and new-onset diabetes after transplant (NODAT).


Urinary tract infections (UTIs), pneumonia, and sepsis occur in 10% to 30% of recipients in the first year after a kidney transplant. Analysis of infection diagnoses among Medicare-insured US kidney transplant recipients in 2000 to 2011 demonstrated an association with increased mortality in the first-year after transplant, ranging from 41% (aHR, 1.41; 95% CI, 1.25 to 1.56) for UTI alone, 6-fold risk for pneumonia, 12-fold risk for sepsis, and 34-fold risk (aHR, 34.38;, 95% CI, 30.35 to 38.95) for those with all three infections in the first year. Infections also significantly increase the first-year cost of kidney transplant care by $17,691 UTI alone, $40,000 to $50,000 for pneumonia or sepsis alone, and $134,773 for those with UTI, pneumonia. and sepsis in this period. Clinical and economic effects persist in years 2 to 3 posttransplant.


Viral-derived malignancies, such as lymphoma, Kaposi sarcoma, lip cancer, and genitourinary tract cancer, are substantially more common in transplant patients than age-adjusted estimates in the general population or patients with chronic kidney disease and ESRD. Cancer has become second only to cardiovascular disease (CVD) as the leading cause of posttransplant mortality, surpassing death from infection. Furthermore, although the risk for death from CVD appears to be stable or even decreasing despite higher comorbidity burdens among transplant recipients, cancer mortality after kidney transplant appears to be increasing over time. In addition to viral-linked cancers, there is an increased frequency of nonmelanoma skin cancers and certain solid organ tumors (including kidney, prostate, and colon carcinoma) compared with nontransplant populations. In a recent study of Medicare-insured US transplant recipients, the cumulative incidence of cancer diagnosed by 3 years posttransplant was 5.7% for nonmelanoma skin cancers, 1.9% for viral-linked, and 6.3% for almost all other cancers. Viral-linked cancer was associated with more than threefold increased risk in subsequent mortality within 3 years after transplant, and nearly twice the mortality risk after year 3. Nonmelanoma skin cancer was associated with 33% higher mortality beyond the third year posttransplant.


Cancer also significantly increases the costs of posttransplant care. Newly diagnosed viral-linked cancer was associated with incremental costs, after adjustment for other recipient and donor characteristics. A diagnosis of a viral-linked cancer resulted in $22,000 to $27,000 per year higher inpatient costs and $9000 to $11,000 per year higher outpatient costs per case. A newly diagnosed “other” cancer was associated with $14,500 to $18,000 per year higher inpatient expenses and $8000 to $9000 per year higher outpatient costs. Nonmelanoma skin cancers was associated only with increased outpatient expenditures, and the cost impact rose from approximately $1400 to $2000 per year in the year of diagnosis to $2500 to $2800 per year in subsequent years. Overall, cancer accounted for 3% to 5.5% of total inpatient Medicare expenditures and 1.5% to 3.3% of outpatient expenditures in the first 3 years posttransplant ( Fig. 34.6 ).




FIG. 34.6


Cost effects of posttransplant cancer. NMSC, nonmelanoma skin cancer.

Reproduced with permission from Dharnidharka VR, Naik AS, Axelrod D, et al. Clinical and economic consequences of early cancer after kidney transplantation in contemporary practice. Transplantation . 2017;101:858-866.


The risk for NODAT has been increasing with the incidence of obesity and racial minorities in the recipient population. The risk is highest in the first year after transplant, ranging from 15% to 30%. Subsequent annual incidence is approximately 5% per year. Risk factors for NODAT include potentially modifiable (e.g., BMI) as well as nonmodifiable factors (e.g., race/ethnicity). NODAT has been associated with adverse outcomes after transplantation, including graft failure and death, as well as rejection, infection, and cardiovascular complications including myocardial infarction (MI) and congestive heart failure. NODAT also increases the cost of posttransplant care. The risk for developing NODAT is associated with African American race, Hispanic ethnicity, obesity, HCV infection, and pretransplant glucose intolerance. Multiple immunosuppressive agents have been implicated, but risk is highest with steroids and tacrolimus, particularly in African Americans.


A population-based analysis of US kidney transplant recipients (2000 to 2011) demonstrated variation in the risk for posttransplant complications over 3 years according to initial immunosuppression regimen ( Fig. 34.7 ). Compared with a regimen of thymoglobulin induction and maintenance tacrolimus, mycophenolate and prednisone, sirolimus-based immunosuppression was associated with increases in the 3-year risks for pneumonia (aHR, 1.45), sepsis (aHR, 1.40), diabetes (aHR, 1.20), acute rejection (aHR, 1.33), graft failure (aHR, 1.78), and patient death (aHR, 1.40), but 29% lower risk for skin cancer. Cyclosporine-based immunosuppression was associated with increased risks for pneumonia (aHR, 1.17), sepsis (aHR, 1.16), acute rejection (aHR, 1.43), and graft failure (aHR, 1.39), but 17% less risk for diabetes. Steroid-free immunosuppression was associated with the 11% reduced risk for pneumonia, 20% reduced risk for sepsis, and 33% reduced risk for diabetes, but 35% higher risk for graft failure.


Feb 24, 2019 | Posted by in NEPHROLOGY | Comments Off on The Epidemiology, Outcomes, and Costs of Contemporary Kidney Transplantation
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